Unveiling the Role of DNA Methylation in Kidney Transplantation: Novel Perspectives toward Biomarker Identification

Agodi, Antonella; Barchitta, Martina; Maugeri, Andrea; Basile, Guido; Zamboni, Matilde; Bernardini, Giulia; Corona, Daniela; Veroux, Massimiliano

doi:https://doi.org/10.1155/2019/1602539

BioMed Research International

On this page

Abstract Introduction Conclusions Conflicts of Interest Acknowledgments References Copyright Related Articles

Special Issue

Recent Advances in Understanding the Role of Genomic and Epigenomic Factors in Noncommunicable Diseases

View this Special Issue

Review Article | Open Access

Volume 2019 | Article ID 1602539 | https://doi.org/10.1155/2019/1602539

Unveiling the Role of DNA Methylation in Kidney Transplantation: Novel Perspectives toward Biomarker Identification

Antonella Agodi,¹Martina Barchitta,¹Andrea Maugeri,¹Guido Basile,²Matilde Zamboni,³Giulia Bernardini,³Daniela Corona,³and Massimiliano Veroux¹

Guest Editor: Kaiissar Mannoor

Received06 Nov 2018

Accepted30 Dec 2018

Published15 Jan 2019

Abstract

The burden of chronic kidney disease is dramatically rising, making it a major public health concern worldwide. Kidney transplantation is now the best treatment for patients with end-stage renal disease. Although kidney transplantation may improve survival and quality of life, its long-term results are hampered by immune- and/or non-immune-mediated complications. Thus, the identification of transplanted patients with a higher risk of posttransplant complications has become a big challenge for public health. However, current biomarkers of posttransplant complications have a poor predictive value, rising the need to explore novel approaches for the management of transplant patient. In this review we summarize the emerging literature about DNA methylation in kidney transplant complications, in order to highlight its perspectives toward biomarker identification. In the forthcoming future the monitoring of DNA methylation in kidney transplant patients could become a plausible strategy toward the prevention and/or treatment of kidney transplant complications.

1. Introduction

The burden of chronic kidney disease (CKD), in terms of human suffering and economic costs, is dramatically rising, making it a major public health concern worldwide [1]. The management of end-stage renal disease (ESRD) patients requires life-saving dialysis or kidney transplantation. Patients receiving renal replacement therapy are appraised at more than 1.4 million worldwide, with an estimated 8% increasing incidence each year [2]. The main reasons of this raise are ageing of populations and the consequent increasing incidence of type 2 diabetes mellitus and hypertension, which are the key risk factors for CKD [3].

Kidney transplantation currently remains the best replacement therapy for patients with irreversible ESRD [4], since it is associated with improved survival and quality of life compared to hemodialysis [5], but either immune- or non-immune-mediated complications significantly contribute to the higher morbidity of transplant patients [5]. While short-term kidney graft survival after transplantation has continuously improved over recent years [5], current evidence reports less marked improvements in long-term outcomes [6–10]. Several factors may affect transplant outcomes, including donor age, alloimmune response, ischemia-reperfusion injury, interstitial fibrosis of the allograft, recipient comorbidity, degree of human leukocyte antigen mismatch and polymorphisms in immunologic and nonimmunologic genes [11–14]. More recently, a particular consideration has been given to genomic and epigenomic differences between the donor and the recipient, which encompass 3.5 to 10 million genetic variants and substantial epigenetic variations related to ethnicity, environment, and lifestyles [15–17]. Blood-based biomarkers have been widely proposed as potential predictive and diagnostic biomarkers, allowing the early identification of patients at high risk of transplant rejection and other adverse outcomes. The study of epigenetic mechanisms—including DNA methylation, histone modification, and noncoding RNA—is getting a lot of interest in this field of research, as reported by previous reviews [18–20].

In this review we provide an overview on how DNA methylation affects development and progression of CKD and we summarize the emerging literature about DNA methylation in kidney transplant complications. Finally, we discuss the perspectives and the clinical usefulness of DNA methylation changes as biomarkers of kidney transplant complications.

2. Epigenetics

Epigenetic mechanisms regulate gene expression without altering the DNA sequence. These molecular processes characterize the epigenome, which is dynamic in response to environmental stressors, modifiable during cell differentiation, and heritable in daughter cells [21]. There are several epigenetic mechanisms, which have been extensively reviewed by Portela and Esteller [22], affecting chromatin condensation, thereby regulating gene expression [23]: histone modifications (e.g., methylation or acetylation), noncoding RNA (e.g., siRNAs, lncRNAs, miRNAs), and DNA methylation [24].

The first lines of evidence on the role of epigenetics have been pointed out by cancer research, with several studies and meta-analyses demonstrating that epigenetic mechanisms regulate tumour suppressor genes silencing, activation of oncogenes, and increased chromosomal instability [25–29]. DNA methylation almost exclusively occurs within CpG islands—short sequences in gene promoters and regulatory regions that typically contain about 5-10 CpG dinucleotides per 100 bp [30]. In mammals, DNA methylation process is mediated by the activity of three DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b).

3. DNA Methylation and Chronic Kidney Disease

Aberrant DNA methylation has been also described in other chronic diseases, such as cardiovascular disease, neurodegenerative diseases, diabetes and its complications, obesity, and CKD [31–38]. The latter has been recently associated with changes in the DNA methylation profile by in vivo and epidemiological studies [39]. Evidence from animal models indicated that in utero restriction of calories, proteins, and oxygen was linked to reduced nephron number, hypertension, and microalbuminuria. The influence of the intrauterine environment on the foetal epigenetic programming might explain foetal origin of adult diseases [40–42]. Beyond developmental programming, metabolic changes might also affect CKD development and long-term health. For instance, epidemiologic studies showed that the hyperglycaemia-related risk of diabetic kidney disease persisted even when metabolic control was restored. The discovery of the long-lasting effect of hyperglycaemia was the breakthrough for the development of the “metabolic memory” theory, particularly in the context of diabetic nephropathy [43, 44]. Consistently, the comparison between saliva samples of diabetic patients with or without end-stage kidney disease identified 187 genes that were differentially methylated, out of which 39 were involved in kidney development or diabetic nephropathy [45].

Recently, Smyth and colleagues compared DNA methylation of 485,577 CpG sites in blood samples between 255 CKD patients and 152 healthy controls [46]. Interestingly, they found aberrant DNA methylation of genes with known biological function in CKD (i.e., CUX1, ELMO1, FKBP5, INHBA-AS1, PTPRN2, and PRKAG2 genes). The relationship between PRKAG2 and CKD has also been confirmed by a meta-analysis of genomewide association data [47]. In addition, the Chronic Renal Insufficiency genomewide study compared the DNA methylation profiles of blood samples among patients classified by different glomerular filtration rates. The authors identified several differentially methylated regions in genes that were associated with kidney functions, including those involved in the epithelial to mesenchymal transition pathway (i.e., NPHP4, IQSEC1, and TCF3) [48].

Several lines of evidence also suggested the role of DNA methylation in kidney fibrosis progression. Stenvinkel and colleagues analysed DNA methylation of blood samples in CKD patients to evaluate the association between renal function, surrogate markers of inflammation, and aberrant DNA methylation. The authors concluded that stable CKD patients with no evidence of inflammation had comparable DNA methylation levels with age- and sex-matched controls, while end-stage kidney disease patients with higher inflammation exhibited DNA hypermethylation [49].

4. DNA Methylation in Kidney Transplantation

The identification of subgroups of transplant patients at higher risk of posttransplant complications has become a big challenge for public health, since it might improve long-term outcomes. However, until now, biomarkers of posttransplant complications have poor predictive value, rising the need to explore novel approaches for the management of transplant patient [20]. The dynamism of the epigenome and the long-lasting effect in response to environmental stimuli make the epigenetic mechanisms a suitable field of research for either biomarker discovery or the development of novel therapeutic strategies [18]. Overall, it has been acknowledged that epigenetic mechanisms play a crucial role in the multiple biological events involved in posttransplant complications, such as alloimmune response, ischemia/reperfusion (I/R) injury, and kidney graft fibrosis [18, 50]. It is also worth mentioning that both the recipient and the donor continuously undergo dynamic epigenetics modifications, even before transplantation [51, 52]. Meht and colleagues first described the usefulness of epigenetic modifications as rejection biomarkers [53]. The authors compared the methylation status of the promoters of DAPK and CALCA genes in urinary DNA from deceased or living donor kidney transplant recipients after 48 hours from the transplantation, and 65 healthy controls. CALCA hypermethylation was more frequently reported in kidney transplant recipients compared with healthy controls and, in addition, CALCA methylation was more frequent in kidney transplant recipients from deceased than from living donors. Interestingly, there was a nonsignificant trend toward CALCA hypermethylation in patients with biopsy-proven acute tubular necrosis, when compared with acute rejection and delayed or immediate graft function [53].

4.1. DNA Methylation and Alloimmune Response

Epigenetic mechanisms might also affect the immune response of the recipient, which is a crucial driver of the alloresponse to the graft [54–57]. Although the use of immunosuppressive drugs improved the short-term kidney graft survival and decreased the incidence of acute graft rejection, the latter still remains accountable for one-tenth of graft loss [5]. The activation of immune cells relies on integrated pathways that in turn are tightly regulated by transcription factors and chromatin remodelers [58]. As extensively reviewed by Mas and colleagues [19], the regulation of gene transcription by epigenetic mechanisms might determine cell plasticity and the strength of posttransplant immune responses.

The major histocompatibility complex (MHC) encodes glycoproteins, which present antigens to the immune system, and its expression is fundamental to alloantigen recognition. Both in physiological (i.e., gametes and embryonic cells) and in pathological (i.e., neoplastic cells) conditions, the downregulation of MHC expression confers a degree of protection from the immune system [59]. In acute rejection there is an increase in MHC II glycoproteins within the allograft and recently it has been demonstrated that DNA methylation and histone modifications affected MHC class I and II expression [60]. DNA methylation also modulates T-cell activation through the production of interleukin-2 (IL-2). In fact, the IL-2 promoter is methylated in inactive T cells, while DNA demethylation allows upregulation of IL-2 following simultaneous T-cell receptor and costimulatory signalling [61]. Most of immune cells involved in allograft rejection are influenced by epigenetic factors. Hence, the investigation of DNA methylation profiles of immune cells before and after kidney transplantation might help the discovery of novel potential biomarkers for the clinical management of patients. For instance, epigenetic mechanisms might affect transcription factors, cytokines, and other molecules that are essential to control the transcriptional profiles and functions of memory T-cell [62]. Steinfelder and colleagues demonstrated that demethylation of the CCR6 gene, which encodes for a chemokine receptor in memory CD4+ T cells, enabled the migration toward the renal proximal tubular epithelial cells [63]. Several studies also demonstrated that epigenetic mechanisms modulated the cytolytic activity of natural killer (NK) cells, which are important in promoting rejection or tolerance [64], by regulating the expression of several NK cell receptors (i.e., KIR, NCRs, and NKG2D) and cytotoxic molecules (i.e., GRZ and PRF) [65, 66]. Others reported the complex epigenetic regulatory systems that modulated the differentiation of hematopoietic stem cells into antibody-producing B cells and antibody production [67–70]. However, most of studies focused on Foxp3, which encodes the transcription factor Scurfin. Foxp3 regulates development and function of CD25+CD4+ regulatory T () cells [71], which in turn maintain immunological self-tolerance and reduce many immune responses [72, 73]. These cells are mainly produced in the thymus as a functionally mature T-cell subpopulation specialized for immune suppression. In line with other genes, methylation of CpG sites within the Foxp3 gene leads to gene silencing whereas complete demethylation is necessary for stable and continuous Foxp3 expression [19]. Interestingly, subpopulations of cells differ in the methylation of the -specific demethylated region within the Foxp3 gene [74]: while -specific demethylated region is methylated in naive CD4+ CD25− T cells, activated CD4+ T cells, and TGF-β–induced adaptive cells, they are demethylated in natural cells [74]. The main role of Foxp3+ natural cells is to suppress several effectors of inflammation, such as T helper () 1, 2, and 17 cells [72, 73]. As comprehensively reviewed by Wilson and colleagues, there are also several lines of evidence demonstrating that chromatin conformation and DNA methylation at lineage restricted cytokine, transcription factor genes, and their regulatory elements in cells both reflect and affect their development and functions [75].

4.2. DNA Methylation and Ischemia-Reperfusion Injury

Several studies proposed that ischemia-reperfusion injury might cause DNA methylation changes in the donor organ. During the ischemic period—in several clinical settings including kidney transplantation—tissues are deprived of oxygen and nutrients required to maintain physiological metabolism and energy homeostasis [76]. In kidney transplantation, the ischemia-reperfusion injury causes a series of pathological responses ranging from inflammation and fibrosis to cell and organ graft injury [76–78]. Pratt and colleagues were the first to propose that modifications of methylated CpG sites may occur as a result of prolonged ischemia-reperfusion injury in kidney transplantation [79], which is in turn associated with chronic nephropathy posttransplantation. In a rodent model of kidney transplantation, they demonstrated that prolonged cold ischemia in rat kidneys caused demethylation of a specific CpG site within the IFN-γ response element resident in the promoter region of complement component 3 (C3) gene [79]. Loss of transcriptional repression of this gene contributes to provide a plausible explanation for the accentuated immunologic injury, which often follows protracted ischemia of the allograft.

4.3. DNA Methylation and Kidney Graft Fibrosis

Progressive interstitial fibrosis is the crucial final pathway in renal destruction in either native or transplanted kidneys. Its pathogenesis is complex and comprises both immune- and non-immune-mediated mechanisms, culminating in interstitial fibrosis, tubular atrophy, and progressive loss of graft function. Similar to wound repair, fibrosis is triggered by an injury and characterized by the deposition of extracellular matrix through activated fibroblasts but conversely it can progress even after the injury has disappeared [80]. Fibrogenesis is the result of complex interactions among the different involved cell types which is coordinated by an extensive network of growth factors and signalling pathways [81]. Mechanisms that contribute to the maintenance of the profibrotic environment have not been well elucidated, but there is emerging evidence for the effects of epigenetics on gene expression and kidney fibrogenesis. Several lines of evidence demonstrated the role of DNA methylation in an abnormal wound healing process that resulted in fibrogenesis in CKD [48, 82]. However, few preclinical studies reported that DNA methylation might activate the fibrogenesis process in the kidney [83], suggesting a possible role for oxidative stress and inflammatory cytokines [84]. A genomewide methylation study of tubule epithelial cells identified 5000 differentially methylated CpG sites between CKD and control patients [82]. Interestingly, functional annotation analysis revealed that most of these regions were within or near developmental and profibrotic genes and that their methylation level correlated with the expression of many profibrotic genes [85]. In addition, a genomewide methylation study of fibroblasts identified 12 genes that were hypermethylated in fibrotic but not in nonfibrotic kidney biopsies [86]. Among these genes, hypermethylation of RASAL1—encoding an inhibitor of the Ras oncoprotein—was investigated further, since its silencing led to fibroblast activation by increased Ras-GTP activity. Notably, in vivo studies demonstrated that kidney fibrosis is ameliorated in DNMT1+/− mice [86], suggesting that RASAL1 hypermethylation was mediated by DNMT1. To uncover the molecular mechanisms that characterized kidney allografts, Bontha and colleagues applied an integrative multiomics approach in biopsies collected 24 months after transplantation. The authors reported hypomethylation of CpG sites within genes involved in activation of CD8+ and CD4+ T cells and MHC genes, and hypermethylation of genes related to metabolic functions, integrity, and structure of kidney [80].

4.4. DNA Methylation and Other Long-Term Complications after Kidney Transplantation

Aberrant DNA methylation is also studied for predicting long-term complications after kidney transplantation. For instance, transplant recipients are more likely to develop cutaneous squamous cell carcinoma (cSCC) [87, 88], for which immunosuppressive treatment seems to be a significant risk factor. Interestingly, Sherston and colleagues investigated methylation of -specific demethylated region within the Foxp3 gene as a marker for cSCC in kidney transplant recipients [89]. The authors followed 58 survivors of a cohort of long-term kidney transplant patients, with and without skin cancer [89]. They found a significant increase in the proportion of demethylated CD4+FOXP3+ cells in patients who had previously developed cSCC. Although these results highlighted the methylation of -specific demethylated region as a potential biomarker for cSCC posttransplantation [89], the use of peripheral blood mononuclear cells instead of sorted cells may represent a limitation of the study. More recently, Peters and colleagues aimed to determine differentially methylated regions in T cells and their role in the development of cSCC in transplant patients [90]. Before transplantation, they compared DNA methylation of T cells between 27 recipients who developed a de novo cSCC and 27 who did not manifest cSCC. The authors found different methylation status in regulatory genomic and bivalent enhancer regions that coded for a zinc-finger protein (i.e., ZNF577) and a protein involved in T-cell migration (i.e., FLOT1), respectively [90]. While the DNA methylation status remained relatively stable in the majority of regions, it significantly changed in 9 differentially methylated regions after transplantation [90], and this could have a long-lasting effect on posttransplant cSCC development.

Recently, the effects of epigenetic mechanisms in cellular and molecular pathways involved in the pathogenesis of cardiorenal syndromes have been proposed [91]. CKD is associated with accumulation of uremic toxins and enhanced oxidative stress, which in turn might affect epigenetic signatures, including DNA methylation. Interestingly, it has been demonstrated that global hypermethylation is independently associated with cardiovascular mortality in patients with CKD [49]. Hypertension is one of the most common complications in kidney transplant recipients, increasing the risk of graft loss and other cardiovascular diseases. In these patients, treatment with angiotensin II (Ang II) blockers for preventing or treating hypertension is closely associated with improved survival. An in vivo study demonstrated that DNA methylation modulated the recipient vascular Ang II receptor (AT1R) gene expression, which in turn increased the vascular contractility in response to Ang II [92]. Another complication in kidney transplant recipients is the new-onset diabetes after transplantation (NODAT), which increases the risk of cardiovascular disease, infections, graft loss, and mortality [93, 94]. A recent genomewide DNA methylation analysis of adipose tissue found no significant difference in global DNA methylation between NODAT patients and healthy controls. However, patients who developed NODAT exhibited aberrant DNA methylation in 900 regions that were involved in insulin resistance, type 2 diabetes, and inflammation. These findings suggested that changes in DNA methylation of adipose tissue might increase infiltration of immune cells with consequent insulin resistance and inflammation, in patients who finally developed NODAT [95].

5. Conclusions

Uncovering the clinical potential of DNA methylation in CKD and complications after kidney transplantation is one of the main challenges toward the management of kidney transplant recipients. While aberrant DNA methylation has been plenty described in CKD by in vivo and epidemiological studies, further research is needed to discover novel potential biomarkers for kidney transplant rejection and complications. Our review highlights the fact that research behind the role of DNA methylation in kidney transplantation has so far exclusively been in the area of basic research, using in vitro or in vivo candidate-gene studies. Few studies provided evidence that epigenetic modifications might affect the individual risk to develop posttransplant complications. Biomarker validation also offers the possibility of identifying novel therapeutic targets. In fact, epigenetic drugs—especially DNA methylating or demethylating agents—are becoming available in oncology, and their potential to maintain functions and integrity of the transplanted organ should be investigated. Furthermore, combined with routine clinical tests, the identification of biomarkers will contribute to an improvement of the patient management. Accordingly, further translational studies should be encouraged to transfer the above-mentioned knowledge to the clinic. In the forthcoming future the monitoring of DNA methylation in kidney transplant patients could become a plausible strategy toward the prevention and/or treatment of kidney transplant complications in the clinical setting and could be useful for identifying those patients who are at higher risk of developing a cardiovascular complication after transplantation, which is the leading cause of death in kidney transplant recipients.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was partially supported by the Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, Italy (Piano Triennale di Sviluppo delle Attività di Ricerca Scientifica del Dipartimento 2016–18).

References

D. E. Weiner, “Public Health Consequences of Chronic Kidney Disease,” Clinical Pharmacology & Therapeutics, vol. 86, no. 5, pp. 566–569, 2009.
View at: Publisher Site | Google Scholar
A. Schieppati and G. Remuzzi, “Chronic renal diseases as a public health problem: Epidemiology, social, and economic implications,” Kidney International Supplements, vol. 68, no. 98, pp. S7–S10, 2005.
View at: Publisher Site | Google Scholar
S. Moeller, S. Gioberge, and G. Brown, “ESRD patients in 2001: Global overview of patients, treatment modalities and development trends,” Nephrology Dialysis Transplantation, vol. 17, no. 12, pp. 2071–2076, 2002.
View at: Publisher Site | Google Scholar
D. J. Lo, B. Kaplan, and A. D. Kirk, “Biomarkers for kidney transplant rejection,” Nature Reviews Nephrology, vol. 10, no. 4, pp. 215–225, 2014.
View at: Publisher Site | Google Scholar
A. J. Matas, J. M. Smith, M. A. Skeans et al. et al., “OPTN/SRTR 2012 annual data report: Kidney,” American Journal of Transplantation, vol. 14, 1, pp. 11–44, 2014.
View at: Publisher Site | Google Scholar
M. Veroux, D. Corona, and P. Veroux, “Kidney transplantation: Future challenges,” Minerva Chirurgica, vol. 64, no. 1, pp. 75–100, 2009.
View at: Google Scholar
J. Pascual, M. J. Pérez-Sáez, M. Mir, and M. Crespo, “Chronic renal allograft injury: Early detection, accurate diagnosis and management,” Transplantation Reviews, vol. 26, no. 4, pp. 280–290, 2012.
View at: Publisher Site | Google Scholar
J. M. Campistol, I. N. Boletis, J. Dantal et al., “Chronic allograft nephropathy--a clinical syndrome: early detection and the potential role of proliferation signal inhibitors,” Clinical Transplantation, vol. 23, no. 6, pp. 769–777, 2009.
View at: Publisher Site | Google Scholar
B. J. Nankivell and D. R. Kuypers, “Diagnosis and prevention of chronic kidney allograft loss,” The Lancet, vol. 378, no. 9800, pp. 1428–1437, 2011.
View at: Publisher Site | Google Scholar
S. A. Lodhi, K. E. Lamb, and H. Meier-Kriesche, “Improving Long-Term Outcomes for Transplant Patients: Making the Case for Long-Term Disease-Specific and Multidisciplinary Research,” American Journal of Transplantation, vol. 11, no. 10, pp. 2264-2265, 2011.
View at: Publisher Site | Google Scholar
M. Veroux, G. Grosso, D. Corona et al., “Age is an important predictor of kidney transplantation outcome,” Nephrology Dialysis Transplantation, vol. 27, no. 4, pp. 1663–1671, 2012.
View at: Publisher Site | Google Scholar
A. E. Courtney, P. T. McNamee, and A. P. Maxwell, “The evolution of renal transplantation in clinical practice: for better, for worse?” QJM: An International Journal of Medicine, vol. 101, no. 12, pp. 967–978, 2008.
View at: Publisher Site | Google Scholar
J. Moore, A. J. McKnight, M. J. Simmonds et al. et al., “Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure,” JAMA2010, vol. 303, pp. 1282–1287, 2010.
View at: Google Scholar
A. Thakkinstian, S. Dmitrienko, M. Gerbase-DeLima et al. et al., “Association between cytokine gene polymorphisms and outcomes in renal transplantation: A meta-analysis of individual patient data,” Nephrology Dialysis Transplantation, vol. 23, no. 9, pp. 3017–3023, 2008.
View at: Publisher Site | Google Scholar
G. R. Abecasis, D. Altshuler, A. Auton et al., “A map of human genome variation from population-scale sequencing,” Nature, vol. 467, pp. 1061–1073, 2010.
View at: Google Scholar
O. Carja, J. L. MacIsaac, S. M. Mah et al., “Worldwide patterns of human epigenetic variation,” Nature Ecology & Evolution, vol. 1, no. 10, pp. 1577–1583, 2017.
View at: Publisher Site | Google Scholar
A. Agodi, M. Barchitta, A. Quattrocchi et al., “Low fruit consumption and folate deficiency are associated with LINE-1 hypomethylation in women of a cancer-free population,” Genes & Nutrition, vol. 10, article 480, 2015.
View at: Publisher Site | Google Scholar
J. A. McCaughan, A. J. McKnight, A. E. Courtney, and A. P. Maxwell, “Epigenetics: Time to translate into transplantation,” Transplantation Journal, vol. 94, no. 1, pp. 1–7, 2012.
View at: Publisher Site | Google Scholar
V. R. Mas, T. H. Le, and D. G. Maluf, “Epigenetics in kidney transplantation: Current evidence, predictions, and future research directions,” Transplantation, vol. 100, no. 1, pp. 23–38, 2016.
View at: Publisher Site | Google Scholar
F. S. Peters, O. C. Manintveld, M. G. Betjes, C. C. Baan, and K. Boer, “Clinical potential of DNA methylation in organ transplantation,” The Journal of Heart and Lung Transplantation, vol. 35, no. 7, pp. 843–850, 2016.
View at: Publisher Site | Google Scholar
S. S. Hammoud, B. R. Cairns, and D. A. Jones, “Epigenetic regulation of colon cancer and intestinal stem cells,” Current Opinion in Cell Biology, vol. 25, no. 2, pp. 177–183, 2013.
View at: Publisher Site | Google Scholar
A. Portela and M. Esteller, “Epigenetic modifications and human disease,” Nature Biotechnology, vol. 28, no. 10, pp. 1057–1068, 2010.
View at: Publisher Site | Google Scholar
J. Baird, C. Jacob, M. Barker et al., “Developmental origins of health and disease: A lifecourse approach to the prevention of non-communicable diseases,” Healthcare, vol. 5, no. 1, p. 14, 2017.
View at: Publisher Site | Google Scholar
A. D. Goldberg, C. D. Allis, and E. Bernstein, “Epigenetics: A landscape takes shape,” Cell, vol. 128, no. 4, pp. 635–638, 2007.
View at: Publisher Site | Google Scholar
M. Barchitta, A. Quattrocchi, A. Maugeri, M. Vinciguerra, and A. Agodi, “LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: A systematic review and meta-analysis,” PLoS ONE, vol. 9, no. 10, Article ID e109478, 2014.
View at: Publisher Site | Google Scholar
A. Agodi, M. Barchitta, A. Quattrocchi, A. Maugeri, M. Vinciguerra, and R. A. Calogero, “DAPK1 Promoter Methylation and Cervical Cancer Risk: A Systematic Review and a Meta-Analysis,” PLoS ONE, vol. 10, article e0135078, 2015.
View at: Publisher Site | Google Scholar
M. Barchitta, A. Quattrocchi, A. Maugeri et al., “LINE-1 hypermethylation in white blood cell DNA is associated with high-grade cervical intraepithelial neoplasia,” BMC Cancer, vol. 17, article 601, 2017.
View at: Publisher Site | Google Scholar
A. Eden, F. Gaudet, A. Waghmare, and R. Jaenisch, “Chromosomal instability and tumors promoted by DNA hypomethylation,” Science, vol. 300, article 455, 2003.
View at: Publisher Site | Google Scholar
V. Phé, O. Cussenot, and M. Rouprêt, “Methylated genes as potential biomarkers in prostate cancer,” BJU International, vol. 105, no. 10, pp. 1364–1370, 2010.
View at: Publisher Site | Google Scholar
G. Auclair and M. Weber, “Mechanisms of DNA methylation and demethylation in mammals,” Biochimie, vol. 94, no. 11, pp. 2202–2211, 2012.
View at: Publisher Site | Google Scholar
C. Y. Wang, S. S. Shie, I. C. Hsieh, M. L. Tsai, and M. S. Wen, “FTO modulates circadian rhythms and inhibits the CLOCK-BMAL1-induced transcription,” Biochemical and Biophysical Research Communications, vol. 464, no. 3, pp. 826–832, 2015.
View at: Publisher Site | Google Scholar
R. S. Dwivedi, J. G. Herman, T. A. McCaffrey, and D. S. Raj, “Beyond genetics: Epigenetic code in chronic kidney disease,” Kidney International, vol. 79, no. 1, pp. 23–32, 2011.
View at: Publisher Site | Google Scholar
E. Agardh, A. Lundstig, A. Perfilyev et al., “Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy,” BMC Medicine, vol. 13, article 182, no. 1, 2015.
View at: Publisher Site | Google Scholar
A. Baccarelli, M. Rienstra, and E. J. Benjamin, “Cardiovascular epigenetics: Basic concepts and results from animal and human studies,” Circulation: Cardiovascular Genetics, vol. 3, no. 6, pp. 567–573, 2010.
View at: Publisher Site | Google Scholar
C. G. Bell, A. E. Teschendorff, V. K. Rakyan, A. P. Maxwell, S. Beck, and D. A. Savage, “Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus,” BMC Medical Genomics, vol. 3, article 33, 2010.
View at: Publisher Site | Google Scholar
D. Cui and X. Xu, “DNA methyltransferases, DNA methylation, and age-associated cognitive function,” International Journal of Molecular Sciences, vol. 19, article 1315, no. 5, p. 1315, 2018.
View at: Publisher Site | Google Scholar
A. Maugeri, M. G. Mazzone, F. Giuliano et al., “Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 5407482, 12 pages, 2018.
View at: Publisher Site | Google Scholar
A. Maugeri, M. Barchitta, M. Mazzone, F. Giuliano, G. Basile, and A. Agodi, “Resveratrol modulates SIRT1 and DNMT functions and restores LINE-1 methylation levels in ARPE-19 cells under oxidative stress and inflammation,” International Journal of Molecular Sciences, vol. 19, no. 7, p. 2118, 2018.
View at: Publisher Site | Google Scholar
Y. Ko and K. Susztak, “Epigenomics: The science of no-longer-junk DNA. why study it in chronic kidney disease?” Seminars in Nephrology, vol. 33, no. 4, pp. 354–362, 2013.
View at: Publisher Site | Google Scholar
Y. Seki, L. Williams, P. M. Vuguin, and M. J. Charron, “Minireview: Epigenetic programming of diabetes and obesity: Animal models,” Endocrinology, vol. 153, no. 3, pp. 1031–1038, 2012.
View at: Publisher Site | Google Scholar
M. J. Warner and S. E. Ozanne, “Mechanisms involved in the developmental programming of adulthood disease,” Biochemical Journal, vol. 427, no. 3, pp. 333–347, 2010.
View at: Publisher Site | Google Scholar
G. C. Burdge and K. A. Lillycrop, “Nutrition, epigenetics, and developmental plasticity: Implications for understanding human disease,” Annual Review of Nutrition, vol. 30, no. 1, pp. 315–339, 2010.
View at: Publisher Site | Google Scholar
M. A. Reddy and R. Natarajan, “Epigenetics in diabetic kidney disease,” Journal of the American Society of Nephrology, vol. 22, no. 12, pp. 2182–2185, 2011.
View at: Publisher Site | Google Scholar
M. A. Reddy, J. T. Park, and R. Natarajan, “Epigenetic modifications and diabetic nephropathy,” Kidney Research and Clinical Practice, vol. 31, no. 3, pp. 139–150, 2012.
View at: Publisher Site | Google Scholar
C. Sapienza, J. Lee, J. Powell et al., “DNA methylation profling identifes epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy,” Epigenetics, vol. 6, no. 1, pp. 20–28, 2011.
View at: Publisher Site | Google Scholar
L. J. Smyth, G. J. McKay, A. P. Maxwell, and A. J. McKnight, “DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease,” Epigenetics, vol. 9, no. 3, pp. 366–376, 2014.
View at: Publisher Site | Google Scholar
A. Köttgen, C. Pattaro, C. A. Böger et al. et al., “New loci associated with kidney function and chronic kidney disease,” Nature Genetics, vol. 42, no. 5, pp. 376–384, 2010.
View at: Publisher Site | Google Scholar
M. R. Wing, J. M. Devaney, M. M. Joffe et al., “DNA methylation profile associated with rapid decline in kidney function: Findings from the CRIC Study,” Nephrology Dialysis Transplantation, vol. 29, no. 4, pp. 864–872, 2014.
View at: Publisher Site | Google Scholar
P. Stenvinkel, M. Karimi, S. Johansson et al. et al., “Impact of inflammation on epigenetic DNA methylation - a novel risk factor for cardiovascular disease?” Journal of Internal Medicine, vol. 261, no. 5, pp. 488–499, 2007.
View at: Publisher Site | Google Scholar
Y. Obata, Y. Furusawa, and K. Hase, “Epigenetic modifications of the immune system in health and disease,” Immunology & Cell Biology, vol. 93, no. 3, pp. 226–232, 2015.
View at: Publisher Site | Google Scholar
S. A. LaMere, H. K. Komori, and D. R. Salomon, “New opportunities for organ transplantation research: Epigenetics is likely to be an important determinant of the host immune response,” Epigenomics, vol. 5, no. 3, pp. 243–246, 2013.
View at: Publisher Site | Google Scholar
M. D. Parker, P. A. Chambers, J. P. Lodge, and J. R. Pratt, “Ischemia- reperfusion injury and its influence on the epigenetic modification of the donor kidney genome,” Transplantation, vol. 86, no. 12, pp. 1818–1823, 2008.
View at: Publisher Site | Google Scholar
T. Mehta, M. Hoque, R. Ugarte et al., “Quantitative detection of promoter hypermethylation as a biomarker of acute kidney injury during transplantation,” Transplantation Proceedings, vol. 38, no. 10, pp. 3420–3426, 2006.
View at: Publisher Site | Google Scholar
N. Ohkura, Y. Kitagawa, and S. Sakaguchi, “Development and maintenance of regulatory T cells,” Immunity, vol. 38, no. 3, pp. 414–423, 2013.
View at: Publisher Site | Google Scholar
D. Kumbala and R. Zhang, “Essential concept of transplant immunology for clinical practice,” World Journal of Transplantation, vol. 3, no. 4, pp. 113–118, 2013.
View at: Publisher Site | Google Scholar
B. Youngblood, J. S. Hale, and R. Ahmed, “T-cell memory differentiation: Insights from transcriptional signatures and epigenetics,” The Journal of Immunology, vol. 139, no. 3, pp. 277–284, 2013.
View at: Publisher Site | Google Scholar
J. Barbi, D. Pardoll, and F. Pan, “Treg functional stability and its responsiveness to the microenvironment,” Immunological Reviews, vol. 259, no. 1, pp. 115–139, 2014.
View at: Publisher Site | Google Scholar
M. K. Atianand and K. A. Fitzgerald, “Long non-coding RNAs and control of gene expression in the immune system,” Trends in Molecular Medicine, vol. 20, no. 11, pp. 623–631, 2014.
View at: Publisher Site | Google Scholar
P. J. Van Den Elsen, T. M. Holling, N. Van Der Stoep, and J. M. Boss, “DNA methylation and expression of major histocompatibility complex class I and class II transactivator genes in human developmental tumor cells and in T cell malignancies,” Clinical Immunology, vol. 109, no. 1, pp. 46–52, 2003.
View at: Publisher Site | Google Scholar
M. Barrett, A. D. Milton, J. Barrett et al., “Needle biopsy evaluation of class II major histocompatibility complex antigen expression for the differential diagnosis of cyclosporine nephrotoxicity from kidney graft rejection,” Transplantation, vol. 44, no. 2, pp. 223–227, 1987.
View at: Publisher Site | Google Scholar
D. R. Fitzpatrick and C. B. Wilson, “Methylation and demethylation in the regulation of genes, cells, and responses in the immune system,” Clinical Immunology, vol. 109, no. 1, pp. 37–45, 2003.
View at: Publisher Site | Google Scholar
N.-P. Weng, Y. Araki, and K. Subedi, “The molecular basis of the memory T cell response: Differential gene expression and its epigenetic regulation,” Nature Reviews Immunology, vol. 12, no. 4, pp. 306–315, 2012.
View at: Publisher Site | Google Scholar
S. Steinfelder, S. Floess, D. Engelbert et al. et al., “Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells,” Blood, vol. 117, no. 10, pp. 2839–2846, 2011.
View at: Publisher Site | Google Scholar
J. Villard, “The role of natural killer cells in human solid organ and tissue transplantation,” Journal of Innate Immunity, vol. 3, no. 4, pp. 395–402, 2011.
View at: Publisher Site | Google Scholar
H. Ogbomo, M. Michaelis, J. Kreuter, H. W. Doerr, and J. Cinatl, “Histone deacetylase inhibitors suppress natural killer cell cytolytic activity,” FEBS Letters, vol. 581, no. 7, pp. 1317–1322, 2007.
View at: Publisher Site | Google Scholar
G. Li, M. Yu, C. M. Weyand, and J. J. Goronzy, “Epigenetic regulation of killer immunoglobulin-like receptor expression in T cells,” Blood, vol. 114, no. 16, pp. 3422–3430, 2009.
View at: Publisher Site | Google Scholar
J. Ramírez, K. Lukin, and J. Hagman, “From hematopoietic progenitors to B cells: Mechanisms of lineage restriction and commitment,” Current Opinion in Immunology, vol. 22, no. 2, pp. 177–184, 2010.
View at: Publisher Site | Google Scholar
B. Barneda-Zahonero, L. Roman-Gonzalez, O. Collazo, T. Mahmoudi, and M. Parra, “Epigenetic Regulation of B Lymphocyte Differentiation, Transdifferentiation, and Reprogramming,” Comparative and Functional Genomics, vol. 2012, Article ID 564381, 10 pages, 2012.
View at: Publisher Site | Google Scholar
M. Parra, “Epigenetic events during B lymphocyte development,” Epigenetics, vol. 4, no. 7, pp. 462–468, 2009.
View at: Publisher Site | Google Scholar
J. Rodríguez-Ubreva, L. Ciudad, D. Gómez-Cabrero et al., “Pre-B cell to macrophage transdifferentiation without significant promoter DNA methylation changes,” Nucleic Acids Research, vol. 40, no. 5, pp. 1954–1968, 2012.
View at: Publisher Site | Google Scholar
G. Lal and J. S. Bromberg, “Epigenetic mechanisms of regulation of Foxp3 expression,” Blood, vol. 114, no. 18, pp. 3727–3735, 2009.
View at: Publisher Site | Google Scholar
P. Sagoo, G. Lombardi, and R. I. Lechler, “Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation,” Frontiers in Immunology, vol. 3, article 184, 2012.
View at: Publisher Site | Google Scholar
H. Fan, P. Cao, D. S. Game, F. Dazzi, Z. Liu, and S. Jiang, “Regulatory T cell therapy for the induction of clinical organ transplantation tolerance,” Seminars in Immunology, vol. 23, no. 6, pp. 453–461, 2011.
View at: Publisher Site | Google Scholar
O. Bestard, L. Cuñetti, J. M. Cruzado et al. et al., “Intragraft regulatory T cells in protocol biopsies retain Foxp3 demethylation and are protective biomarkers for kidney graft outcome,” American Journal of Transplantation, vol. 11, no. 10, pp. 2162–2172, 2011.
View at: Publisher Site | Google Scholar
C. B. Wilson, E. Rowell, and M. Sekimata, “Epigenetic control of T-helper-cell differentiation,” Nature Reviews Immunology, vol. 9, no. 2, pp. 91–105, 2009.
View at: Publisher Site | Google Scholar
J. Menke, D. Sollinger, B. Schamberger, U. Heemann, and J. Lutz, “The effect of ischemia/reperfusion on the kidney graft,” Current Opinion in Organ Transplantation, vol. 19, no. 4, pp. 395–400, 2014.
View at: Publisher Site | Google Scholar
P. Cravedi and P. S. Heeger, “Complement as a multifaceted modulator of kidney transplant injury,” The Journal of Clinical Investigation, vol. 124, no. 6, pp. 2348–2354, 2014.
View at: Publisher Site | Google Scholar
C. Ponticelli, “Ischaemia-reperfusion injury: A major protagonist in kidney transplantation,” Nephrology Dialysis Transplantation, vol. 29, no. 6, pp. 1134–1140, 2014.
View at: Publisher Site | Google Scholar
J. R. Pratt, M. D. Parker, L. J. Affleck et al., “Ischemic epigenetics and the transplanted kidney,” Transplantation Proceedings, vol. 38, no. 10, pp. 3344–3346, 2006.
View at: Publisher Site | Google Scholar
S. V. Bontha, D. G. Maluf, K. J. Archer et al., “Effects of DNA methylation on progression to interstitial fibrosis and tubular atrophy in renal allograft biopsies: A multi-omics approach,” American Journal of Transplantation, vol. 17, no. 12, pp. 3060–3075, 2017.
View at: Publisher Site | Google Scholar
X. Li and S. Zhuang, “Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation,” Fibrogenesis Tissue Repair, vol. 7, article 15, no. 1, 2014.
View at: Publisher Site | Google Scholar
Y.-A. Ko, D. Mohtat, M. Suzuki et al. et al., “Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development,” Genome Biology, vol. 14, article R108, 2013.
View at: Publisher Site | Google Scholar
E. M. Zeisberg and M. Zeisberg, “The role of promoter hypermethylation in fibroblast activation and fibrogenesis,” The Journal of Pathology, vol. 229, no. 2, pp. 264–273, 2013.
View at: Publisher Site | Google Scholar
I. Fonseca, H. Reguengo, M. Almeida et al., “Oxidative stress in kidney transplantation: Malondialdehyde is an early predictive marker of graft dysfunction,” Transplantation, vol. 97, no. 10, pp. 1058–1065, 2014.
View at: Publisher Site | Google Scholar
K. I. Woroniecka, A. S. D. Park, D. Mohtat, D. B. Thomas, J. M. Pullman, and K. Susztak, “Transcriptome analysis of human diabetic kidney disease,” Diabetes, vol. 60, no. 9, pp. 2354–2369, 2011.
View at: Publisher Site | Google Scholar
W. Bechtel, S. McGoohan, E. M. Zeisberg et al., “Methylation determines fibroblast activation and fibrogenesis in the kidney,” Nature Medicine, vol. 16, no. 5, pp. 544–550, 2010.
View at: Publisher Site | Google Scholar
C. M. Vajdic, S. P. McDonald, M. R. E. McCredie et al., “Cancer incidence before and after kidney transplantation,” Journal of the American Medical Association, vol. 296, no. 23, pp. 2823–2831, 2006.
View at: Publisher Site | Google Scholar
P. Piselli, D. Serraino, G. P. Segoloni et al., “Risk of de novo cancers after transplantation: Results from a cohort of 7217 kidney transplant recipients, Italy 1997–2009,” European Journal of Cancer, vol. 49, no. 2, pp. 336–344, 2013.
View at: Publisher Site | Google Scholar
S. N. Sherston, K. Vogt, S. Schlickeiser, B. Sawitzki, P. N. Harden, and K. J. Wood, “Demethylation of the TSDR is a marker of squamous cell carcinoma in transplant recipients,” American Journal of Transplantation, vol. 14, no. 11, pp. 2617–2622, 2014.
View at: Publisher Site | Google Scholar
F. S. Peters, A. M. Peeters, P. R. Mandaviya et al., “Differentially methylated regions in T cells identify kidney transplant patients at risk for de novo skin cancer,” Clinical Epigenetics, vol. 10, article 81, 2018.
View at: Publisher Site | Google Scholar
G. M. Virzì, A. Clementi, A. Brocca, M. de Cal, and C. Ronco, “Epigenetics: A potential key mechanism involved in the pathogenesis of cardiorenal syndromes,” Journal of Nephrology, vol. 31, no. 3, pp. 333–341, 2018.
View at: Publisher Site | Google Scholar
Y. Zhao, Q. Zhu, S. Sun et al., “Renal transplantation increases angiotensin II receptor-mediated vascular contractility associated with changes of epigenetic mechanisms,” International Journal of Molecular Medicine, vol. 41, pp. 2375–2388, 2018.
View at: Publisher Site | Google Scholar
F. G. Cosio, T. E. Pesavento, K. Osei, M. L. Henry, and R. M. Ferguson, “Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years,” Kidney International, vol. 59, no. 2, pp. 732–737, 2001.
View at: Publisher Site | Google Scholar
M. Veroux, T. Tallarita, D. Corona et al., “Conversion to sirolimus therapy in kidney transplant recipients with new onset diabetes mellitus after transplantation,” Clinical and Developmental Immunology, vol. 2013, Article ID 496974, 7 pages, 2013.
View at: Publisher Site | Google Scholar
S. Baheti, P. Singh, Y. Zhang et al., “Adipose tissue DNA methylome changes in development of new-onset diabetes after kidney transplantation,” Epigenomics, vol. 9, no. 11, pp. 1423–1435, 2017.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2019 Antonella Agodi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1981

Downloads

1541

Citations